Chromone derivatives

ABSTRACT

The present invention relates to novel chromone derivatives having effective anti-allergic action, which are shown by the following general formula (I)   wherein m is 0, 1 or 2, n is 0 or 1, and each of R&#39;&#39;s represents halogen atom, nitro, hydroxy, alkyl including the case where the two alkyl groups on any two adjacent carbon atoms at positions 5, 6, 7 and 8 form a benzene ring with the two carbon atoms, lower alkoxy, acyloxy, carboxy which may be esterified, carboxamide which may be unsubstituted or substituted by at least one alkyl or aralkyl group, or amino group which may be unsubstituted or substituted by acyl group or hydrocarbon residue, and their pharmaceutically acceptable salts.

United States Patent [191 Nohara et al.

[ July 22, 1975 [22] Filed: Apr. 10, 1973 [21] Appl. No.: 349,848

[30] Foreign Application Priority Data Apr. 12, 1972 Japan 47-37235 [52] US. Cl 260/240 E; 424/269; 260/308 D;

[51] Int. Cl C07d 55/00 [58] Field of Search 260/308 D, 240 E [56] References Cited FOREIGN PATENTS OR APPLICATIONS 2,105,191 8/1971 Germany I. 260/308 D Primary Examiner-John D. Randolph [57] ABSTRACT The present invention relates to novel chromone derivatives having effective anti-allergic action, which are shown by the following general formula (I) wherein m is O, l or 2, n is 0 or 1, and each of R's represents halogen atom, nitro, hydroxy, alkyl including the case where the two alkyl groups on any two adjacent carbon atoms at positions 5, 6, 7 and 8 form a benzene ring with the two carbon atoms, lower alkoxy, acyloxy, carboxy which may be esterified, carboxamide which may be unsubstituted or substituted by at least one alkyl or aralkyl group, or amino group which may be unsubstituted or substituted by acyl group or hydrocarbon residue, and their pharmaceutically acceptable salts.

45 Claims, No Drawings CHROMONE DERIVATIVES The present invention relates also to a process for the production of these chromone derivatives.

Hitherto, there have been known many kinds of'antihistamine agents, and some of them have been put into practical use. However, aforesaid known antihistamine agents are not very satisfactory in view of one or more of such drawbacks as showing rather low anti-allergic activity and rather high toxicity and causing side effects (e.g. sedation, cardiac stimulation and headache.) upon long-term administration. Moreover, most of the known anti-histamine agents show only antagonism towards histamine released or produced in aliving body and, thus, they. are not satisfactory as a medicine for treating allergic disease which is caused by other allergy mediating substances, e.g. SRSA(slow reacting substance of anaphylaxis) than histamine. a

The inhibition of the secretion of chemical mediators, such as SRSA and histamine, is very effective for the treatment of allergic disease, e.g. bronchial asthma.

Hithertofore, however, no one has, succeeded in synthesizing any compound in compliance with this purpose, at least from a practical or an industrial point of view.

Under thesecircumstances, present inventors have made extensive studies and succeeded in synthesizing specific new chromone derivatives (I) defined above, which have never previously been synthesized.

Moreover, the present inventors have also unexpectedly found that these compounds have a very strong ac tion in preventing the secretionof SRSA and histamine from the cells of a living body, and they also show quite a low toxicity; furthermore they show the above actions effectively even upon oral administration.

, In view of these characteristics, the present compounds can be used as an effective medicine for preventing and/or treating allergic diseases, especially bronchial asthma and rhinitis, by means of oral administration, The present invention has been accomplished on the basis or these findings.

Thus, the principal object of the present invention is to provide the chromone derivatives (I) and their pharmaceutically acceptable salts useful as effective antiallergic agents, and another object of the present invention is to provide a method for the production of these compounds.

In the general f ormula (I), thealkyl group represented. by the symbol R may be any of straight, 'b ranchcdor cyclic ones having I to 6 carbon atoms. Typical examples of the alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, cyclopentyl, hexyl and cyclohexyl. Among them, for practical purposes, lower alkyl groups having 1 to 3 carbon atoms are preferred. The lower alkoxy group represented by the symbol R may be preferably that having I to 4 carbon atoms, such as mcthoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy. The acyloxy group represented by the symbol R may be lower alkyl carbonyloxy group whose alkyl moiety is that having I to 3 carbon atoms, and aryl carbonyloxy group. Typical examples of the acyloxy group may be acetoxy, propionyloxy, butyryloxy and benzoyloxy. The carboxygroup R which may be esterified is represented by the formula COOR', wherein R represents hydrogen atom, lower alkyl group having l to 3 carbon atoms or aralkyl group. The

2 lower alkyl group represented by the symbol R is that having 1 to 3 carbon atoms, such as methyl, ethyl, propyl' and isopropyl, and typical examples of the aralkyl group represented by thesymbolR may be benzyl, phenethyl. The alkyl substituted carboxamide group represented by the symbol R includes monoor dialkyl substituted ones whose alkyl moiety is lower alkyl one having Ho 3 carbon atoms and monoor diaralkyl (e.g. benzyl) substituted ones. Typical examples of these groups may. be N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl vcarboxamide, N,N-diethylcarboxamide, N-propyl carboxamide, N-benzyl carboxamide and N,N-dibenzyl carboxamide. The acylsubstituted amino group represented by the symbol R includes an amino group substituted by lower alkylcarbonyl group whose alkyl moietyis that having 1 to 3 carbon atoms and an amino group. substituted by arylcarbonylgroup. Typical examples of these group may be acetylamino, propionylamino, butyrylamino and benzoylamino. The hydrocarbon-substituted amino group represented by the symbol R includes .monoor di-lower alkyl substituted ones whose alkyl moiety is that having 1 to 3 carbon atoms, monoor diary] (efg. phenyl, naphthyl) substituted ones and: monoor diaralkyl (eg. benzyl, phenethyl) substituted ones. Typical examples of these groups may be methylamino, ethylamino, propylamino, iso propylamino, dimethylamino, diethylamino, dipropylami'no, phenylamino, diphenylamino, benzylamino or phenethylamino. The halogen atom represented. by the symbol R may be chlorine, bromine iodine and fluorine." 4 I In the present invention, the object compounds of the general formula (I) are produced by reacting the compound II) i wherein R, m and n have the same meaning as defined above, with hydrazoic acidora salt thereof.

The salt of hydrazoic acid e'mployable in the present invention includes salts of hydrazoic acid with alkali metals oralkaline earth metals such as lithium azide, sodium azide, potassium azide, magnesium azide, calcium azide, barium azide and strontium azide; the salts of hydrazoic acid with other metals capable of forming salts with hydrazoic acid, such as, aluminum azide, tin azide, Zinc azide and titanium azide; and the salts of hydrazoic acid with ammonia or organic amines (e.g. aniline, quinoline, imidazole).

In the reaction of the present invention, the salts of hydrazoic acid with alkali metals also can be employed in combination with, for example, a Lewis acid such as aluminum chloride, stannic chloride, zinc chloride or titanium tetrachloride or ammonium chloride.

The amount of hydrazoic acid, a salt thereof or the Lewis acid or its equivalent used in combination with the salt of hydrazoic acid is generally about 1 to 7 moles per mole of the starting compound (II) for practical purposes.

Generally; the reaction is desirably carried out in an organic solvent. The solvent is exemplified by hydrocarbons such as benzene, toluene, petroleum ether; others such as tetrahydrofuran, dioxane. ethyl ether and ethylene glycol dimethyl ether; dimethylformamide; formamide; dimethylsulfoxide. While the reaction conditions including temperature and time factors are largely optional, it is generally convenient to carry out the reaction at room temperature to about 150C for about 1 hour to about 2 days.

When a salt of hydrazoic acid is used as one of the starting compounds, the reaction of this invention yields the object compound of the general formula (I) in the form of the salt corresponding to the hydrazoate used due to the acid function of the tetrazole ring. This salt, however, can be easily converted to the object compound (I) possessing a free tetrazole ring by treating it with a suitable acid (e.g. a mineral acid such as hydrochloric acid or sulfuric acid).

The object compound of the general formula (I) which can be obtained in the foregoing manner can be isolated and purified by procedures which are conventional per se (e.g. extraction, chromatography, recrystallization, etc.).

When the object compound of the general formula (I) is substituted by alkoxy or acyloxy group(s), these alkoxy and acyloxy groups can be converted to hydroxyl groups by procedures of conventional dealkylation or deacylation (e.g. hydrolysis with a hydrohalogenic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid and with a mineral acid such as sulfuric acid).

Moreover, when the object compound of the general formula (I) is substituted by acylamino group(s), the acylamino group can be converted to amino group(s) under conditions similar to the above conditions of hydrolysis which are conventionally used for the cleavage of amide bonds. On the contrary, when the object compound of the general formula (I) is substituted by hydroxy, amino or carboxy group(s), these groups can be converted to acyloxy, acylamino. esterified carboxy or carboxamide group which may be substituted by conventional acylation, esterification or amidation. Further, when the object compound of the general formula (I) has a free tetrazole ring, it can be converted to an organic amine salt, alkali metal salt or ammonium salt by reacting the compound of the general formula (I) with an organic amine. e.g. ethanolamine. dimeth- SteplB) NH OH 4 ylephedrine, l-(3.S-dihydroxyphenyD-L- isopropylaminoethanol, isoproterenol, dextromethorphan, I-Ietrazan (diethylcarbamazine), diethylamine or triethylamine; an alkali metal hydroxide, e.g. sodium hydroxide or potassium hydroxide; alkali metal carbonate, e.g. sodium carbonate or potassium carbonate; or

ammonia in a per se conventional manner, e.g. by ad-- mixing and heating the reactants together in the presence of an appropriate solvent (e.g. water, alcohol, dioxane, tetrahydrofuran).

The thus produced object compound (I) or their pharmaceutically acceptable salts, above all, the salts with the organic amines mentioned above specifically, have an effective anti-allergic action and are useful as medicines for allergic diseases such as allergic bronchial asthma, allergic dermatitis, allergic rhinitis and hay fever.

Further, since the alkali metal salts and organic amine salts of the compound (I) are highly soluble in water, and the solutions so formed are stable, they lend themselves well to manufacturing such pharmaceutical preparations as injections and solutions.

When the compounds of the general formula (I) or pharmaceutically acceptable salt thereof are employed as anti-allergic agents for treating or preventing the abovementioned allergic diseases, these compounds are administered per se or in the form of a pharmaceutically acceptable composition in admixture with suitable and conventional carriers or adjuvants.

The pharmaceutical composition may take the form of tablets, capsules, granules, powders, solution, injections, ointments, sprays or aerosol inhalants, and can be administered orally or parenterally. Especially, the compounds of the present invention show effective action even upon oral administration, and therefore they are very advantageous from a practical point of view.

The usual daily doses of the present compounds lie in the range of about I to about 500 mg. more precisely of about 50 to 500 mg. upon oral administration and about 1 to about 200 mg. upon parenteral administration per adult human.

One of the starting compounds (ll) of the present invention may be produced by, for example, the following procedure:

OH SteplA) l R) COCH Vilsmeiel' CHO reagent 0 (III) 1 Continued StapiC) C N CH =C H C N 0 COOH wherein R and m have the same meaning as defined 10 ether, ethyl ether, etc., and alcohols such as methanol, above. ethanol, etc. The base is exemplified by tertiary amines The reaction of the Step (A) is conducted by reacting such as trimethylamine, triethylamine, N- a compound of the general formula (IV) with Vilsmeier methylpiperidine, N-methylmorpholine, N- reagent, which consists f e uiv l nt m le( f di methylpyrrolidine,etc;heteroaromatic compound such methylformamide and acid chloride such as phosphoas pyridine, 2-methylpyridine, 3-methylpyridine, quinrus oxychloride, tetrachloropyrophosphate, thionyllin 2-methylquinoline, imidazole, 2- chloride, phosgene, phosphorus pentachloride, etc., in methylimidazole, etc. Among these compounds, the presence or absence of a suitable inert solvent. As heteroaromatic compounds are the most desirable the solvent, any solvent which does not restrict the refrom all practical purposes. These bases may also be action may be employed. Typical examples of the solexpected to function as the reaction solvent. The reacvent are benzene, diethyl ether, petroleum benzine, tion conditions including the reaction temperature and chloroform or mixtures thereof. time cannot be stated in general terms, for they depend The amount of the dimethylformamide and the acid upon the type of solvent and starting compounds to be chloride of Vilsmeier reagent is usually at least not less used. Generally speaking, it is desirable to conduct the than 2 moles, preferably 10 to 12 moles per mole of a reaction at room temperature to a temperature near compound of the general formula p i ly the boiling point of the solvent used, although one may Th reaction can Proceed at room temperature Under conduct the reaction at a reduced temperature, if reatmospheric Pressure, if necessary, y be carried quired. The reaction time is usually about several minout under heating up to the boiling point of dimethylutes to about 10 h formamide or of the solvent used or cooling down to -30C or under heating and elevated pressure. The re- Inc n ly, the abOVe COTHPOlmd wherein R iS action time varies with the reaction conditions such as amino group which may be substituted by alkyl group temperature, pressure or kinds of acid chloride and solmay be produced by, for example, the following procevent used, but is generally from 25 minutes to 24- hours. dures:

( /OH R'CHO Rum ;-\r 93 NO 'K i I I COOH- reduction CH5,

(A) COCIZE, (wherein R lower alkyl or hydrogen) (ii) ,OH OH N02 lb cg convention- 11 2 lgjL i 5 reduction of 5 111 no j. ."oup

The reaction of Step (B) is preferably conducted by The above compound (IV) wherein R is amino group reacting a compound of the general formula (III) with which is substituted by alkyl, aralkyl or acyl group may hydroxylamine in the presence'of a suitable solvent also be produced by reacting the compound (C) with such as alcohols (e.g. methanol, ethanol and prepanol) conventional alkylating, aralkylating or acylating or ether (e.g. dioxane and tetrahydrofuran). t,

While hydroxylamine may be the free base, it is preferable to employ the correspondinghydrochloride. The amount of this reactant is usually about 1 to about 4 moles per mole of the compound (III).

For example, the compound (IV) wherein R is dimethylamino group is produced as follows;

Into a mixture of 10 weight parts of 2-hydroxy-5- The reaction conditions including the reaction temmtro'acetophenone m 200 volume parts of methanol perature and time are largely optional, it is usually suf- 22 v( lume parts of 37:70 aqueous formaldehyde ficient to conduct the reaction at 0 to 150C for l to hmon Introduced at 25 C 5500 volume parts of 24 hours drogen 1n the presence of 2 weight parts of palladium- The reaction of Step (C) is conducted by reacting a carbon catalyst and 5 volume parts of ZN-HCI. The recompound of the general formula (III) with cyanoace- Sultam filtered and concentrated to gwe tic acid in a solvent and in the presence of a base. The dimethylminoLhydroxyacetophenone as Yellow amount of cyanoacetic acid to be used in this reaction dies meltmg at 75046-500 is usually about 1 to 2 moles per mole of the compound For a further explanation of the present invention,

of the general formula (III). the following References and Examples are given, The solvent is exemplified by hydrocarbons such as wherein the word part(s) is based on weight unless benzene, petroleum ether, etc.; ethers such as methyl otherwise noted and the relationship between part(s)" and volume part(s) corresponds to that between gram(s) and milliliter(s).

REFERENCES Reaction of Step(A In 80 volume parts of dimethylformamide are dissolved 25 parts of orthohydroxyacetophenone and, while the solution is externally cooled to about 20C with dry ice-acetone, 80 volume parts of tetrachloropyrophosphoric acid are added dropwise to the solution. The resulting mixture is stirred at room temperature for 13 hours. Then, the reaction mixture is poured into ice water and the resulting crystals are recovered by filtration, washed with water and ethanol and finally recrystallized from acetone. The procedure yields of 4-oxo-4H-l-benzopyran-3-carboxaldehyde as colorless crystals melting at 152153C.

Analysis for C l-l O Calcd. C, 73.97; H, 4.14. Found C, 73.88; H, 4.23.

By the procedure similar to the above reference, the following compounds are synthesized.

Starting Product Crystal form Melting materials Recrystalli- Point(C) zation solvent Z-Hydroxy-S- 6-Chloro-4- White scales 166-168 chloroacetooxo-4H-1- phenone benzopyran- Dimethyl- 3-carboxformamide aldehyde Acetone 2Hydroxy-5- 6-Nitro-4 Pale yellow 163-164 nitroacetooxo-4H-lprisms phenone benzopyran Dimethyl- 3-carboxformamide aldehyde Acetone Z-Hydroxy- 6,8-Dimethyl- Colorless 186-187 3 ,S-dimethyl 4-oxo-4H- 1 needles acetophenone benzopyran- Dimethyl Dimethyl- 3-carboxformamide formamide aldehyde Acetone 2-Hydroxy- 6,8-Dibromo- Colorless 177-178 3 ,S-dibromo 4oxo-4H- 1 needles acetophenone benzopyran-3- Dimethylcarboxformamide aldehyde Acetone 2-Hydroxy-5- 6-Dimethyl- Yellow 153-1545 dimethyl amino-4-oxoneedles aminoaceto- 4H- 1 -benzo- Dimethyl phenone pyran-3 formamide Dimethylcarboxformamide aldehyde Acetone Z-Hydroxy-S- 6-lsopropyl- Yellow 98-995 isopropyl 4-oxo-4H- 1 needles acetophenone benzopyran- Ethylace- Dimethyl- 3-carboxtate formamide aldehyde Petroleum ether 2-Hydroxy-5- 6-Propyl-4- Pale yellow 100-102 propylacetooxo-4H- 1- scales phenone benzopyran- Ligroin Dimethyl- 3-carbox- Ethylformamide aldehyde acetate Z-Hydroxy-S- 6-n-Butyl-4- Colorless 86.5-88.5 n-butyloxo-4H-lneedles acetophenone benzopyran- Dimethyl- 3-carbox- Ligroin formamide aldehyde Cyclohexane Z-Hydroxy-S- 6-methyl-4- Colorless 174-175 methylacctooxo-4H-l' scales phenone benzophran- Dimethyl- 3-carbox formamide aldehyde acetone 2-Hydroxy-4- 7-Methoxy-4- Pale yellow 188-190 methoxyoxo-4H-1 needles acetophenone benzopyran- Dimethyl- 3-carboxformamide aldehyde Acetone 2-Hydroxy-5- 6-Methoxy-4- Pale yellow 165-166 methoxy oxo-4H-1- plates acetophenone benzopyran-3- Dimethylcarbox- -Continued Starting Product Crystal form Melting materials Recrystalli- Point( C) zation solvent formamide aldehyde Acetone 2-l-lydroxy-6- 5-Methoxy-4- Pale yellow 115-1 16 methoxyoxo-4l-1- l plates acetophenone benzopyran-3- Dimethylcarboxformamide aldehyde Acetone 2-Hydroxy-5- 6-Ethyl-4- Colorless 109-1 1 1 ethyloxo-4H-1- acetophenone benzopyran-3- scales Dimethylcarboxaldehyde Ethylformamide acetate 2-Hydroxo-6- 5-Acetoxy-4- Colorless 174.5-1 76.5 acetoxyoxo-4H-1- needles acetophenone benzopyran-3- Dimethylcarboxformamide aldehyde Acetone 2-1-lydroxy-4- 7-Acetoxy-4- Pale yellow 155-156 acetoxyoxo-4H- 1 needles acetophenone benzopyran-3- Dimethylcarboxformamide aldehyde Acetone 2-l-lydroxy-5- 6-Carboxy-4- Colorless 27 1.5-273.5 carboxyoxo-4H-1- crystals (decomp.) acetophenone benzopyran-3- Dimethylcarboxformamide aldehyde Acetone 2,4-Dihydroxy 7-Hydroxy-4- Yellow 2665-2685 acetophenone oxo-4H- 1- prisms (decomp.) Dimethylbenzopyran-3- DMF formamide carbox- Acetone aldehyde H O 2-Hydroxy-5- 6-Acetamino- Pale yellow 231-233 acetamino- 4-oxo-4H- 1 powder acetophenone benzopyran-3- Dimethylcarboxformamide aldehyde Acetone REACTIONS OF Step(B) AND (C):

Reference 1 2.52 Parts of 4-oxo-4H-l-benzopyran-3- carboxaldehyde are admixed well with 2.10 parts ofhydroxylamine hydrochloride, followed by the addition of 30 volume parts of weight ethyl alcohol and 0.5 volume part of concentrated hydrochloric acid. The whole mixture is refluxed for 6 hours and cooled. The resulting precipitate is recovered by filtration, treated with activated carbon and recrystallized from ethanol. This procedure yields 4-oxo-4H-l-benzopyran-3- carbonitrile as colorless crystals.

Melting point: l77-l78C.

Analysis for C H NO Calcd. C, 70.17; H, 2.95; N, 8.19. Found C, 70.00; H, 2.80; N, 8.13.

Reference 2 A mixture of 10.44 parts of 4-oxo-4l-l-l-benzopyran- 3-carboxaldehyde and 5.4 parts of cyanoacetic acid are heated in an oil bath at C, and to the mixture 25 volume parts of pyridine are added dropwise over about 30 seconds, after which time the whole mixture is further heated for 8 minutes. After cooling, the separated crystals are recovered by filtration, treated with activated carbon and recrystallized three times from ethanol. This procedure yields trans-3-(4-oxo-4H-lbenzopyran-3-yl)-acrylonitrile as pale-yellowish prisms. Melting point: 192-194C.

Analysis for C H NO Calcd. C, 73.09; H, 3.58; N, 7.10. Found C, 73.48; H, 3.60; N, 7.01.

By procedures similar to the above procedure, the following compounds are synthesized.

' -Continued Starting Product Crystal form Melting Starting Product Crystal form Melting compound Recrystalli-, point compound Recrystallipoint zation (C) 5 zation (C) solvent J V solvent 6-Methyl-4- 6-Methyl-4- Colorless 1525- j 'fi 53? 1 644 65 OXO-DH-loxo-4l-1-1- needles 153.5 PY box W 3 benzopyranbenzopyran-3- 1 f; h A car B 3-carboxcarbonitrile 2 e h l 8 D. h l C l enzene aldehyde Ethanol 1O g s ra gf 6-Ethy1-4- 6-Ethyl-4- Colorless es oxo-4H- 1 oxo-4H- l crystals 123-124 enzopyran'za' y f [96-198 benzopyran-3- benzopyran-3- ig g carbommle A carboxcarbonitrile a e y e cetone aldehyde Ethanol 7-Acetoxy-4- 7-Acetoxy-4- Colorless 6-Chloro-4- 6-Ch1oro-4- Yellow oxo-4H-loxo-4H-lprisms 210-213 benzopyran' benzopyrfmf crystals benzopyran 3 benzopyran 3 3-carbox- 3-carbonltrlle 182-183 carbox carbonimlc aldehyde Ethanol (decomp.) aldehyde Methanol 7-Benzoyloxy 7-Benzoyloxy Plates 6-Methoxy-4- 6-Methoxy-4- Colorless ox0-4l-ll oxo-4H- l needles 194-195 200'202 benzopyran-3- benzopyran-3- Ethanol carbox carbonimle carboxcarbonltrlle tetrahydroaldehyde Ethanol aldehyde fura 5. 1 Colorless 6,7-Dlhydroxy 6,7-Dlhydroxy Pale brown 41. 0X 4H 1 plates -4-oxo-4H- 1- -4-oxo-4l-l-1- powder benzopyram}. benzopymn 3 55 benzopyranbenzopyran-lihlgher Garbo Carbonitrilc Ethanob 3-carboxcarbomtrlle Dlmethylthan aldehyde hexane aldehyde formamide- 300 7-n-Butoxy-4- 7-n-Butoxy- Pale yellow water oxo-4H-1- 4-oxo-4H-1- plates 120-121 benzopyran-3- benzopyran-3- carboxcarbonitrile Benzenealdehyde n-Hexane 6-Dimethyl- 6-Dimethyl- Yellow needles 167-168 amino-4-oxoamino-4-oxo- 4H-1-benzo- 4H-l-benzo- Chloroformi 7 EXAMPLE 1 2x23 ziggfg t 22:: To 100 volume parts of dry tetrahydrofuran are aldehyde added 4.28 parts of comminuted anhydrous aluminum 5: 32: 3}; flfi g fg ggf f 229430 chloride, 2.50 parts of 4-oxo-4il-l benzopyran-3- chmmone Acetone (1600mm carbonltrlle and 4.18 parts of sodlum azlde in this order g ggz lg afgfii g zifi 5: 3:2 35 and, the whole mixture is refluxed under stirring for 23 chwmone v Ethanol hours. Then, to the resulting mixture 35 volume parts g-Cyclohexyl- 6-Cyclohexyl- Pale brown 164465 of 15 weight% hydrochloric -acid' are added, followed gg gg 'g plates by distilling off tetrahydrofural l under reduced'prescarbox 3 carbosure. The resulting solid residue is recovered by filtrag ifgggg I gigfif Pale mx tion and recrystallized from dimethylformamide. This memes 102404 procedure yields 3-( lH-tetrazol-S-yl) chromone-as colg g y g gpy i orless hairy needles. j gggg gg' fj. H Ethane, Melting point: 2s4-2s5c (decomp. with foaming). -lsopropyl- I fi-lsopropyl- Pale yellow H8 120 Analysis for C10H6N4O2. Calcd.-C, 56.07; H, 2.82; N, 35 233; 7 gawk- 26.16. Found c, 56.16; H, 2.60;N, 26.27. carboxcarbonitrile 1 aldehyde Ethanol EXAMPLE 2 7-Methoxy-4- 7-Methoxy-4- Pale yellow oXo 4H 17 needles 191-193 Under stlrrlng, 4.6 parts of; anhydrous aluminum g gy 225 853352 chloride are added to 100 volume parts of dry tetrahyg g Methanol drofuran, followed by the addition of 3.1 1 parts of tran- 6-n-Butyl-4- 6-n-Butyl-4- Colgrless' 54 95 s-3-(4-oxo-41-I-1-benzopyran=3-yl)-acry1onitrile and g:g; g fgi g 'g nee i 4.5 parts of sodium azide. The whole mixture is recarbox- 3 carbofluxed for 28 hours and, then, 35 volume parts of 15 g gfgi x 55 weight% hydrochloric acid are added to the resulting memes 124426 mixture, followed by distilling off tetrahydrofuran lcozrggs ranag:g;t)H; 1 under reduced pressure. The resulting residue is recovaldehyde f ered by filtration and recrystallized from methanol, 6N 4 giki le 4 C I l Benzene dimethylformamide-water and, then, from methanol. Q1232 1 2: 3: 2 23; e55 211413 This procedure yields, trans-l-(4-oxo-41-l-lbenzopyran-3- benzopyran-3- benzopyran-3-y1)-2-( lH-tetrazol-S-yl) ethylene as $285 carbmmle g g gg light-yellow needles. Melting point: 254.5255C- 7-Acetoxy-4- 7 -Hydroxy-4- Colorless pwlth g)- I needles 2 Analysis for C12HgN4O2. Calcd. C, 60.00; 1-1, 3.36; N, benzopyran-3- benzopyran-3- 2 who carbonitrile 3.32. Found C, 59.98; H, 3.25; N, 23.15. Mass specu l elgyde 6 Eh C l l Ethano trum; m/e 240(Mf), 212, 196. g jj, g gfi" gf z By procedures similar to the procedure described .4-oxo- -4-oxoabove, the following compounds are synthesized.

Continued I Starting Product Crystal fonn Melting C-.(Injection) I I compound point(C) (l) I sodium 3-(ll-l-tetrazol-5-yl)- 10 mg.

Recrystalli- I I '6-ethylchron'ione I zation solvent 2) inositol 100 mg. ethyl ch r O m one (3) benzyl alcohol 20 mg.

Monoetha- I I nolamine Ethanol Diethylamine cblofless 223 All ingredients are dissolved in water to make 2.0 m1.

zol 5-yl)-6- salt scales of (hfiSOlUlZlOIl (pl-l 7.5) serving as ll'lJCCtlQIl. elhylchl'omme What we claim is: v

Ethanol- Diethylethylether 1. A compound of the general formula amine N EXAMPLES ll, 0.244 Part of 3-( lH-tetrazol-5-yl)-6- methoxychromone is added to 8 parts of 57- weight hydrojodic acid, and the whole mixture is heated at I I EXAMPLE 6 Some eiramples of practical recipes in which the compounds of this invention are utilized as remedies for an allergic disease are as follows:

A Tablet) (l) 3-( lH-tetrazol-5-yl)-6- mg.

ethylchromone (2) lactose 35 mg. (3) corn starch 150 mg. (4) microcrystalline cellulose 30 mg. (5) magnesium stearate 5 mg. 240 mg.

per tablet (l), (2), (3), quantity of (4) and half quantity of (5) are throughly mixed, and then the mixture is granulated. Remaining quantity of (4) and half of (5) areadded to the granules and compressed into tablets. Thus prepared tablets can further be coated with a suitable coating agent, e.g. sugar.

B.(Capsule) (l) 3-( lH-tetrazol-5-yl)-6- 20 mg.

ethylchromone (2) lactose 102 mg. (3) microcrystalline cellulose 70 mg. (4) magnesium stearate 8 mg. 200 mg. per capsule (l), (2), (3) and half quantity of (4) are throughly mixed, and then the mixture is granulated. Remaining half of (4) is added to the granules and the whole is filled into a gelatin capsule.

wherein m is O, l or 2, n is O or 1, and each of Rs represents halogen atom, nitro, hydroxy, straight or branched alkyl having 1 to 6 carbon atoms, cyclopentyl, cyclohexyl or" butadienylene (CH=)\' Cl-l-CH=Cl-l which forms a benzene ring with any two adjacent carbon atoms at positions 5, 6, 7 and 8, lower alkoxy, RCOO, wherein R is a straight or branched chain alkyl having 1 to 3 carbon atomsfor phenyl, COOR, wherein R is hydrogen alkyl having 1 to 3 carbon atoms, benzyl or phe nethyLcarbQXamide which may be unsubstituted or substituted by atleast one alkyl having 1 to 3 carbon atoms. or b enzyl, or amino group which may be unsubstituted or substituted by RCO, wherein R isa straighter branched chain alkyl having 1 to 3 carbon atoms for phenyl, or alkyl having up to 3 carbon atoms, benzyLphenethyl, phenyl or naphthyl, or-their pharmaceutically acceptable salts.

2. A compound as claimed in claim 1, wherein n is 0,.

3. A compound-as claimedin claim 1, wherein n -is l.

4. A compound asclaimed in claims 2, wherein mv-is 0.

5. A compound as claimed in claims 2, wherein m is l.

6. A compound as claimed in claims 2, wherein m is 2.

7. A compound as claimed in claim 1, wherein R represents a halogen atom.

8. A compound as claimed in claim 1, wherein R represents a straight or branched chain alkyl having 1 to 6 carbon atoms, cyclopentyl or cyclohexyl.

9. A compound as claimed in claim 1, wherein butadienylene (Cl-l=Cl-lCl-l=CH-) forms a benzene ring with any two adjacent carbon atoms at positions 5, 6, 7 and 8.

10. A compound as claimed in claim 1, wherein R represents a lower alkoxy group.

11. A compound as claimed in claim 1, wherein R represents a carboxy group which may be esterified.

12. A compound as claimed in claim 1, wherein R represents an esterified carboxy group shown by the formula COOR' wherein R is a lower alkyl group.

13. A compound as claimed in claim 1, wherein R represents an esterified carboxy group shown by the formula COOR, wherein R is an aralkyl group.

14. A compound as claimed in claim 1, wherein R represents a carboxamide group.

15. A compound as claimed in claim 1, wherein R represents a carboxamide group substituted by alkyl group.

16. A compound as claimed in claim 1, wherein R represents a carboxamide group substituted by aralkyl group.

17. A compound as claimed in claim 1, wherein R represents an amino group.

18. A compound as claimed in claim 1, wherein R represents an acylamino group of the formula RCONH wherein R is straight or branched alkyl having 1 to 3 carbon atoms and phenyl.

19. A compound as claimed in claim 1, wherein R represents an amino group substituted by alkyl having up to 3 carbon atoms, benzyl, phenethyl, phenyl or naphthyl.

20. A compound as claimed in claim 1, wherein R represents an amino group substituted by lower alkyl group.

21. A compound as claimed in claim 1, wherein R represents an amino group substituted by phenyl or naphthyl.

22. A compound as claimed in claim 1, wherein R represents an amino group substituted by aralkyl group.

23. A compound as claimed in claim 1, wherein the compound is 3-( ll-l-tetrazol-S-yl)chromone.

24. A compound as claimed in claim 1, wherein the compound is trans-l-(4-oxo-4H-l-benzopyran-3-yl)-2- (lH-tetrazol-S-yl)ethylene.

25. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-S-yl)-6-methylchromone.

26. A compound as claimed in claim 1, wherein the compound is 3-( ll-l-tetrazol-S-yl)-6-ethylchromone.

27. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-S-yl)-6-chlorochromone.

28. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-5-yl)-6- methoxychromone.

29. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-S-yl)-6-hexylchromone.

30. A compound as claimed in claim 1, wherein the compound is 3-(1l-l-tetrazol-5-yl)-7-nbutoxychromone.

31. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-S -yl)-6- dimethylaminochromone.

32. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-5-yl)-benzo(h)chromone.

33. A compound as claimed in claim 1, wherein the compound is 3-(lH-tetrazol-S-yl)-benzo(f)chromone.

34. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-5-yl)-6- cyclohexylchromone.

35. A compound as claimed in claim 1, wherein the compound is 3-( ll-l-tetrazol-S-yl )-6-npropylchromone.

36. A compound as claimed in claim 1, wherein the compound is 3-( lI-l-tetrazol-5-yl)-6- isopropylchromone.

37. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-5-yl)-7- methoxychromone.

38. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-S-yl)-6-n-butylchromone. 39. A compound as claimed in claim 1, wherein the compound is trans l-( 6-n-butyl-4-oxo-4l-ll benzopyran-3-yl)-2-( lH-tetrazol-S-yl)ethylene.

40. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-S-yl)-6-nitrochromone.

41. A compound as claimed in claim 1, wherein the compound is 3-( lH-tetrazol-5-yl)-7- hydroxychromone.

42. A compound as claimed in claim '2, wherein m is 1 23 A compound as claimed in claim 3 wherein m is 44. A compound as claimed in claim 3 wherein m is :45. A compound as claimed in claim 3 wherein m is 

1. A COMPOUND OF THE GENERAL FORMULA
 2. A compound as claimed in claim 1, wherein n is
 0. 3. A compound as claimed in claim 1, wherein n is
 1. 4. A compound as claimed in claims 2, wherein m is
 0. 5. A compound as claimed in claims 2, wherein m is
 1. 6. A compound as claimed in claims 2, wherein m is
 2. 7. A compound as claimed in claim 1, wherein R represents a halogen atom.
 8. A compound as claimed in claim 1, wherein R represents a straight or branched chain alkyl having 1 to 6 carbon atoms, cyclopentyl or cyclohexyl.
 9. A compound as claimed in claim 1, wherein butadienylene (-CH CH-CH CH-) forms a benzene ring with any two adjacent carbon atoms at positions 5, 6, 7 and
 8. 10. A compound as claimed in claim 1, wherein R represents a lower alkoxy group.
 11. A compound as claimed in claim 1, wherein R represents a carboxy group which may be esterified.
 12. A compound as claimed in claim 1, wherein R represents an esterified carboxy group shown by the formula -COOR'' wherein R'' is a lower alkyl group.
 13. A compound as claimed in claim 1, wherein R represents an esterified carboxy group shown by the formula -COOR'', wherein R'' is an aralkyl group.
 14. A compound as claimed in claim 1, wherein R represents a carboxamide group.
 15. A compound as claimed in claim 1, wherein R represents a carboxamide group substituted by alkyl group.
 16. A compound as claimed in claim 1, wherein R represents a carboxamide group substituted by aralkyl group.
 17. A compound as claimed in claim 1, wherein R represents an amino group.
 18. A compound as claimed in claim 1, wherein R represents an acylamino group of the formula RCONH- wherein R is straight or branched alkyl having 1 to 3 carbon atoms and phenyl.
 19. A compound as claimed in claim 1, wherein R represents an amino group substituted by alkyl having up to 3 carbon atoms, benzyl, phenethyl, phenyl or naphthyl.
 20. A compound as claimed in claim 1, wherein R represents an amino group substituted by lower alkyl group.
 21. A compound as claimed in claim 1, wherein R represents an amino group substituted by phenyl or naphthyl.
 22. A compound as claimed in claim 1, wherein R represents an amino group substituted by aralkyl group.
 23. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)chromone.
 24. A compound as claimed in claim 1, wherein the compound is trans-1-(4-oxo-4H-1-benzopyran-3-yl)-2-(1H-tetrazol-5-yl)ethylene.
 25. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-methylchromone.
 26. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-ethylchromone.
 27. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-chlorochromone.
 28. A compound as claimed in claim 1, wHerein the compound is 3-(1H-tetrazol-5-yl)-6-methoxychromone.
 29. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-hexylchromone.
 30. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-7-n-butoxychromone.
 31. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-dimethylaminochromone.
 32. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-benzo(h)chromone.
 33. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-benzo(f)chromone.
 34. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-cyclohexylchromone.
 35. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-n-propylchromone.
 36. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-isopropylchromone.
 37. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-7-methoxychromone.
 38. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-n-butylchromone.
 39. A compound as claimed in claim 1, wherein the compound is trans 1-(6-n-butyl-4-oxo-4H-1-benzopyran-3-yl)-2-(1H-tetrazol-5-yl)ethylene.
 40. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-6-nitrochromone.
 41. A compound as claimed in claim 1, wherein the compound is 3-(1H-tetrazol-5-yl)-7-hydroxychromone.
 42. A compound as claimed in claim 2, wherein m is 1 or
 2. 43. A compound as claimed in claim 3 wherein m is
 0. 44. A compound as claimed in claim 3 wherein m is
 1. 45. A compound as claimed in claim 3 wherein m is
 2. 